Screening for novel therapeutic agents targeting multidrug-resistant Klebsiella pneumoniae

The occurrence of antimicrobial resistance, a major global health threat, can be attributed to the emergence of multidrug-resistant (MDR) Gram-negative bacteria, such as Klebsiella pneumoniae. To improve the therapeutic arsenal against MDR pathogens, this study evaluated the antibacterial activities of 240 compounds from the Global Health Priority Box (GHPB) against an MDR K. pneumoniae strain. In particular, this study examined the inhibitory concentrations of GHPB compounds and their antimicrobial synergy with polymyxin B (PMB) and effects on membrane permeability, nucleic acid and protein leakage, and the production of reactive oxygen species. Ultra-structural changes were investigated using scanning electron microscopy. The safety of compounds was evaluated using the hemolysis and Caenorhabditis elegans-based assays. Additionally, molecular docking analyses and pharmacokinetic parameter prediction were performed. Two compounds (MMV1794211 (M11) and MMV006187 (M18)) in combination with PMB exerted synergistic antimicrobial effects. The combination of M11 or M18 and PMB was associated with low toxicity. M11 and M18 interacted with DNA gyrase. Pharmacokinetic analysis revealed that M11 and M18 can be administered via the oral and parenteral routes, respectively. These findings suggest that M11 and M18, in combination with PMB are promising candidates for further preclinical evaluation against MDR K. pneumoniae infections.